Fibroblast activation protein α (FAP α) is a dual-specificity dipeptidyl-peptidase and collagenase (Scanlan, M. J. et al. (1994), Proc. Natl. Acad. Sci. USA, 91, 5657-5661). FAP and the well-studied dipeptidyl-peptidase IV (DPP IV, EC 3.4.14.5) are both members of the recently described “DPP IV activity- and/or structure-homologues” (DASH) proteins, comprising enzymes with a common post-proline-cleaving serine dipeptidase mechanism (Sedo, A. and Malik, R. Biochim. Biophys. Acta 2001, 1550, 2, 107-116; P. Bu{hacek over (s)}ek, et al. Int. J. Biochem. Cell Biol. (2004) 36(3), 408-421). FAP has a high degree of homology with DPP-IV, and has been reported to form heterodimers with DPP IV ii vivo.
FAP differs from DPP IV in that its distribution is highly localized and it is not as abundant. Unlike DPP IV, FAP is a tumor-associated antigen that is not expressed in normal tissues; rather, it is only expressed on the tumor-supporting and non-malignant cells comprising the tumor stroma (Folkman, J., et al. Nature (1989) 339, 58-61; Garin-Chesa, P., et al., Proc. Natl. Acad. Sci. USA (1990), 87, 7235-7239; Chen W T, Adv Exp Med Biol (2003), 524, 197-203). There is strong evidence implicating FAP as a tumor stromal marker. FAPα is selectively expressed in reactive stromal fibroblasts of many histological types of human epithelial cancers, granulation tissue of healing wounds, and malignant cells of certain bone and soft tissue sarcomas. Normal adult tissues are generally devoid of detectable FAPα, but some fetal mesenchymal tissues transiently express the protein. In contrast, most of the common types of epithelial cancers, including >90% of breast, non-small-cell lung, and colorectal carcinomas, contain FAPα-reactive stromal fibroblasts (Scanlan et al., loc. cit.). These FAPα+ fibroblasts accompany newly formed tumor blood vessels, forming a distinct cellular compartment interposed between the tumor capillary endothelium and the basal aspect of malignant epithelial cell clusters (Welt et al. (1994) J. Clin. Oncol. 12(6), 1193-1203). While FAPα+ stromal fibroblasts are found in both primary and metastatic carcinomas, the benign and premalignant epithelial lesions tested (Welt et al., loc. cit.), such as fibroadenomas of the breast and colorectal adenomas, only rarely contain FAPα+ stromal cells. The expression profile of FAP suggests that it may play a role in the invasion of normal tissue by a cancerous growth, as well as in tumorigenesis. Therefore, a need exists for the design and synthesis of selective inhibitors of FAP.